"People generally study genome evolution by looking at how the sequence of DNA itself has changed over time, but it turns out that isn't the whole story. Epigenetics can have an impact as well."

In an exciting new publication in PLoS Genetics, CHORI scientists Lucia Carbone, PhD, Pieter de Jong, PhD, David Martin, MD, and their colleagues, demonstrate for the first time by analyzing DNA sequences in the northern white-cheeked gibbon that epigenetic states of repeated elements can impact genome evolution. This new information is important not only for understanding mammalian evolution, but also to discover how epigenetic changes in DNA might cause human disease, such as cancer.

Everyone knows that the phenotypes seen in different individuals - their hair or eye color, for example - are the result of which genotypes, or sequences of DNA, they have inherited from their parents. The idea of epigenetics, however, is that the same DNA sequence might behave differently in different cells, species or individuals within a species.

"Genome evolution is the description of a how a genome changes through evolution, and the way in which you can actually study this is by comparing genomes of different species to discover the most important regions," explains Dr. Carbone. "For example, DNA sequences that are identical in human and mouse are most likely to have an essential function for mammalian organisms."

The advent of epigenetics, however, has raised the question of whether other DNA modifications that don't involved a change in DNA sequence could be influencing genome evolution, as well. The results of the new study, which Dr. Carbone recently presented at one of the most prestigious genome conferences in the world, the Biology of Genomes (Cold Spring Harbor), suggest for the first time that the answer to that question is undoubtedly, Yes.

"We're interested in studying gibbons because while they are evolutionarily very close to us, they have a 20-fold increase in chromosomal rearrangments as compared to humans and other primate species," Dr. Carbone says.

Chromosomal rearrangments occur when two or more chromosomes break and recombine in ways they shouldn't. As Dr. Carbone explains, her goal in the current study was to try to understand why this happened so often during the evolution of gibbon species and possibly identify new mechanisms to explain such chromosome instability. To do so, Dr. Carbone focused on analyzing the DNA breakpoints - those sequences in which the DNA unexpectedly broke and recombined.

"When I looked at the chromosome breakpoint sequences in the gibbon, I couldn't find anything that could explain the higher rate of chromosome rearrangements. The genomic content of these breakpoints did not look any different from what had been found in breakpoints in other primates."

Dr. Carbone didn't give up however: rather than focusing on modifications in the DNA sequence itself, she began to look for epigenetic clues instead. What Dr. Carbone and her colleagues discovered was that the regions associated with the chromosomal rearrangements contained a series of repeats that, while very common in the primate genome in general, are undermethylated in the gibbon specifically.

"Generally undermethylated DNA corresponds to DNA that is "active", allowing the gene after it to be transcribed," explains Dr. Carbone. "Methylated DNA corresponds to DNA that is "inactive," because methylation interferes with the binding of proteins that activate the transcription of a specific gene."

This suggests that it isn't the actual sequence of the repeated DNA that matters, but whether the repeats are in a methylated or unmethylated state - in other words, the cause of the increased chromosomal rearrangemts in the gibbon may be due to epigenetic mechanisms.

"We don't yet know exactly the underlying mechanism, but the reduced methylation of these repeats must somehow be responsible for the higher rate of chromosome breakage," says. Dr Carbone.

The relationship between undermethylated repeats and chromosome rearrangements is of particular interest because recent studies have shown that a similar relationship may be present in cancer cells.

"Either increased or decreased methylation has been a consistent finding in human tumors and it is thought to be associated with chromosome rearrangements; what we find in the gibbon is an indirect way to show that undermethylated repeats may be responsible for genome instability," says Dr. Carbone.

"Now we can actually use the gibbon to create a new model of chromosome evolution that we can apply to other species."